Background: Why are women more susceptible to multiple sclerosis, but men have worse disability p... more Background: Why are women more susceptible to multiple sclerosis, but men have worse disability progression? Sex differences in disease may be due to sex hormones, sex chromosomes, or both. Objective: Determine whether differences in sex chromosomes can contribute to sex differences in multiple sclerosis using experimental autoimmune encephalomyelitis. Methods: Sex chromosome transgenic mice, which permit the study of sex chromosomes not confounded by differences in sex hormones, were used to examine an effect of sex chromosomes on autoimmunity and neurodegeneration, focusing on X chromosome genes. Results: T-lymphocyte DNA methylation studies of the X chromosome gene Foxp3 suggested that maternal versus paternal imprinting of X chromosome genes may underlie sex differences in autoimmunity. Bone marrow chimeras with the same immune system but different sex chromosomes in the central nervous system suggested that differential expression of the X chromosome gene Toll-like receptor 7 i...
Proceedings of the National Academy of Sciences, 2017
Significance Molecular mechanisms underlying distinct disabilities during neurological diseases m... more Significance Molecular mechanisms underlying distinct disabilities during neurological diseases may differ based on the neurological pathway involved. Multiple sclerosis (MS) is multifocal, characterized by distinct disabilities affecting walking, vision, cognition, and fatigue. Neuroprotective treatments tailored for each disability may be more effective than nonspecific treatments aiming to reduce a composite of disabilities in clinical trials. Here, we use the MS model to apply a cell-specific and region-specific gene expression approach to discover targets in distinct neuroanatomic regions. Altered cholesterol synthesis gene expression in astrocytes in spinal cord and optic nerve was identified as a potential target for walking and visual disabilities, respectively. This disability-specific discovery approach represents a strategy for finding neuroprotective treatments for multifocal neurodegenerative diseases.
Introduction: Sex differences in susceptibility to ischemia/reperfusion (I/R) injury have been mo... more Introduction: Sex differences in susceptibility to ischemia/reperfusion (I/R) injury have been mostly attributed to sex hormones. Recently we examined the role of sex chromosomes in sex differences in myocardial I/R injury. We discovered that gonadectomized mice with two X chromosomes (XX or XXY) have ~50% larger infarct size after I/R injury, compared to mice with one X chromosome (XY or XO). Only few X genes escape X inactivation and are expressed higher in XX than XY individuals. Here we examined the role of “X escapee” histone demethylase Kdm6a which is important in cardiac development. Methods: Female mice with a heterozygous global knockout of Kdm6a (Kdm6a+/-) and with 2 copies of Kdm6a (Kdm6a+/+, regular WT) were used. Isolated mouse hearts were subjected to 30 min global normothermic ischemia followed by 60 min reperfusion. RNA-Seq analysis was performed by comparing gene expression in hearts of Kdm6a+/+ vs. Kdm6a+/- females at baseline before ischemia. We calculated an unbi...
In mouse and humans , each tissue has a distinct distribution of M:F ratios, but in each case the... more In mouse and humans , each tissue has a distinct distribution of M:F ratios, but in each case the distribution for X genes (red line) fits closely to the distribution for A genes (dotted black line). LB, lymphoblastoid cell lines. PBM cells, peripheral blood mononuclear cells. Arrows point to regions where the X and A curves diverge, or to the inflection point in the mouse adipose tissue curve.<b>Copyright information:</b>Taken from "Dosage compensation is less effective in birds than in mammals"http://jbiol.com/content/6/1/2Journal of Biology 2007;6(1):2-2.Published online 22 Mar 2007PMCID:PMC2373894.
M:F ratios in zebra finches, in adult brain, liver, and kidney, and brain of post-hatch day 1 (P1... more M:F ratios in zebra finches, in adult brain, liver, and kidney, and brain of post-hatch day 1 (P1). Autosomal genes (A) are represented by the black dotted line, Z genes (Z) by the red line. The vertical dashed line is centered at a M:F ratio of 1 (logratio of 0). M:F ratios of embryonic chick brain, liver and heart. In each case Z genes are expressed at higher M:F ratios than A genes. In (b) the panel on the far right shows distributions for brain of individual chromosomes containing more than 50 genes. In all panels in (a) and (b) the rightmost bin (at the rightmost mark on the abscissa) includes all genes with M:F ratios at that value or greater, and the leftmost bin includes all genes with M:F ratios at that value or smaller. Z:A ratios of five male and five female chicken samples for heart (H), brain (B) and liver (L).<b>Copyright information:</b>Taken from "Dosage compensation is less effective in birds than in mammals"http://jbiol.com/content/6/1/2Journa...
Sex differences in physiology and disease in mammals result from the effects of three classes of ... more Sex differences in physiology and disease in mammals result from the effects of three classes of factors that are inherently unequal in males and females: reversible (activational) effects of gonadal hormones, permanent (organizational) effects of gonadal hormones, and cell-autonomous effects of sex chromosomes, as well as genes driven by these classes of factors. Often, these factors act together to cause sex differences in specific phenotypes, but the relative contribution of each and the interactions among them remain unclear. Here, we used the Four Core Genotypes (FCG) mouse model with or without hormone replacement to distinguish the effects of each class of sex-biasing factors on transcriptome regulation in liver and adipose tissues. We found that the activational hormone levels have the strongest influence on gene expression, followed by the organizational gonadal sex effect and, lastly, sex chromosomal effect, along with interactions among the three factors. Tissue specifici...
Aging is a risk factor for cognitive decline and susceptibility to neurodegenerative diseases. So... more Aging is a risk factor for cognitive decline and susceptibility to neurodegenerative diseases. Some aspects of aging, like the loss of sex hormones, may be preventable. Menopause is associated with cognitive deficits and brain atrophy. Since standard hormone replacement therapy (HRT) does not mitigate these brain aging outcomes, a gap in knowledge involves understanding brain region-specific, cell-specific, and receptor-specific mechanisms underlying this neurodegeneration. Here, cognitive testing and in vivo magnetic resonance imaging demonstrated that ovarian hormones in female mice at midlife protect against hippocampal-dependent cognitive impairment and dorsal hippocampal atrophy. Further, this neuroprotection in females at midlife is lost in mice with selective deletion of estrogen receptor beta (ERβ) in astrocytes, but not neurons. This preclinical evidence identifies ERβ in astrocytes as a novel therapeutic target to prevent hippocampal-dependent cognitive deficits and reduce...
Three different models of MF1 strain mice were studied to measure the effects of gonadal secretio... more Three different models of MF1 strain mice were studied to measure the effects of gonadal secretions and sex chromosome type and number on body weight and composition, and on related metabolic variables such as glucose homeostasis, feeding, and activity. The 3 genetic models varied sex chromosome complement in different ways, as follows: 1) “four core genotypes” mice, comprising XX and XY gonadal males, and XX and XY gonadal females; 2) the XY* model comprising groups similar to XO, XX, XY, and XXY; and 3) a novel model comprising 6 groups having XO, XX, and XY chromosomes with either testes or ovaries. In gonadally intact mice, gonadal males were heavier than gonadal females, but sex chromosome complement also influenced weight. The male/female difference was abolished by adult gonadectomy, after which mice with 2 sex chromosomes (XX or XY) had greater body weight and percentage of body fat than mice with 1 X chromosome. A second sex chromosome of either type, X or Y, had similar ef...
The majority of preclinical biomedical research involves studies of males rather than females. It... more The majority of preclinical biomedical research involves studies of males rather than females. It is thought that researchers have avoided females based on the idea that female traits are more variable than those of males because of cyclic variation in effects of ovarian hormones. To test the assumption of inherently greater female variability, we analyzed 293 microarray datasets measuring gene expression in various tissues of mice and humans, comprising analysis of more than 5 million probes. Meta-analysis showed that on average, male gene expression is slightly more variable than that of females although the difference is small. We also tested if the X chromosome of humans shows greater variability in gene expression in males than in females, as might be expected because of hemizygous exposure of polymorphic X alleles but again found little sex difference. Our analysis supports and extends previous studies reporting no overall greater phenotypic variability in females.
Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain d... more Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain during health, and regional differences in the transcriptome may occur for each cell type during neurodegeneration. Multiple sclerosis (MS) is multifocal, and regional differences in the astrocyte transcriptome occur in experimental autoimmune encephalomyelitis (EAE), an MS model. MS and EAE are characterized by inflammation, demyelination, and axonal damage, with minimal remyelination. Here, RNA-sequencing analysis of MS tissues from six brain regions suggested a focus on oligodendrocyte lineage cells (OLCs) in corpus callosum. Olig1-RiboTag mice were used to determine the translatome of OLCs in vivo in corpus callosum during the remyelination phase of a chronic cuprizone model with axonal damage. Cholesterol-synthesis gene pathways dominated as the top up-regulated pathways in OLCs during remyelination. In EAE, remyelination was induced with estrogen receptor-β (ERβ) ligand treatment, a...
Progressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairme... more Progressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%-70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing-remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol-treated compared to placebo-treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes. Sixty-two estriol- and forty-nine placebo-treated RRMS patients underwent clinical evaluations and brain MRI. Voxel-based morphometry (VBM) was used to evaluate voxelwise GM sparing from high-resolution T1-weighted scans. A region of treatment-induced sparing (TIS) was defined as the areas where GM was spared in estriol- as compared to placeb...
A modern general theory of sex determination and sexual differentiation identifies the factors th... more A modern general theory of sex determination and sexual differentiation identifies the factors that cause sexual bias in gene networks, leading to sex differences in physiology and disease. The primary sex-biasing factors are those encoded on the sex chromosomes that are inherently different in the male and female zygotes. These factors, and downstream factors such as gonadal hormones, act directly on tissues to produce sex differences and antagonize each other to reduce sex differences. Recent studies of mouse models such as the four core genotypes have begun to distinguish between the direct effects of sex chromosome complement (XX vs. XY) and hormonal effects. Several lines of evidence implicate epigenetic processes in the control of sex differences, although a great deal of information is needed about sex differences in the epigenome.
Philosophical Transactions of the Royal Society B: Biological Sciences, 2016
Historically, it was thought that the number of X chromosomes plays little role in causing sex di... more Historically, it was thought that the number of X chromosomes plays little role in causing sex differences in traits. Recently, selected mouse models have been used increasingly to compare mice with the same type of gonad but with one versus two copies of the X chromosome. Study of these models demonstrates that mice with one X chromosome can be strikingly different from those with two X chromosomes, when the differences are not attributable to confounding group differences in gonadal hormones. The number of X chromosomes affects adiposity and metabolic disease, cardiovascular ischaemia/reperfusion injury and behaviour. The effects of X chromosome number are likely the result of inherent differences in expression of X genes that escape inactivation, and are therefore expressed from both X chromosomes in XX mice, resulting in a higher level of expression when two X chromosomes are present. The effects of X chromosome number contribute to sex differences in disease phenotypes, and may...
Background: Why are women more susceptible to multiple sclerosis, but men have worse disability p... more Background: Why are women more susceptible to multiple sclerosis, but men have worse disability progression? Sex differences in disease may be due to sex hormones, sex chromosomes, or both. Objective: Determine whether differences in sex chromosomes can contribute to sex differences in multiple sclerosis using experimental autoimmune encephalomyelitis. Methods: Sex chromosome transgenic mice, which permit the study of sex chromosomes not confounded by differences in sex hormones, were used to examine an effect of sex chromosomes on autoimmunity and neurodegeneration, focusing on X chromosome genes. Results: T-lymphocyte DNA methylation studies of the X chromosome gene Foxp3 suggested that maternal versus paternal imprinting of X chromosome genes may underlie sex differences in autoimmunity. Bone marrow chimeras with the same immune system but different sex chromosomes in the central nervous system suggested that differential expression of the X chromosome gene Toll-like receptor 7 i...
Proceedings of the National Academy of Sciences, 2017
Significance Molecular mechanisms underlying distinct disabilities during neurological diseases m... more Significance Molecular mechanisms underlying distinct disabilities during neurological diseases may differ based on the neurological pathway involved. Multiple sclerosis (MS) is multifocal, characterized by distinct disabilities affecting walking, vision, cognition, and fatigue. Neuroprotective treatments tailored for each disability may be more effective than nonspecific treatments aiming to reduce a composite of disabilities in clinical trials. Here, we use the MS model to apply a cell-specific and region-specific gene expression approach to discover targets in distinct neuroanatomic regions. Altered cholesterol synthesis gene expression in astrocytes in spinal cord and optic nerve was identified as a potential target for walking and visual disabilities, respectively. This disability-specific discovery approach represents a strategy for finding neuroprotective treatments for multifocal neurodegenerative diseases.
Introduction: Sex differences in susceptibility to ischemia/reperfusion (I/R) injury have been mo... more Introduction: Sex differences in susceptibility to ischemia/reperfusion (I/R) injury have been mostly attributed to sex hormones. Recently we examined the role of sex chromosomes in sex differences in myocardial I/R injury. We discovered that gonadectomized mice with two X chromosomes (XX or XXY) have ~50% larger infarct size after I/R injury, compared to mice with one X chromosome (XY or XO). Only few X genes escape X inactivation and are expressed higher in XX than XY individuals. Here we examined the role of “X escapee” histone demethylase Kdm6a which is important in cardiac development. Methods: Female mice with a heterozygous global knockout of Kdm6a (Kdm6a+/-) and with 2 copies of Kdm6a (Kdm6a+/+, regular WT) were used. Isolated mouse hearts were subjected to 30 min global normothermic ischemia followed by 60 min reperfusion. RNA-Seq analysis was performed by comparing gene expression in hearts of Kdm6a+/+ vs. Kdm6a+/- females at baseline before ischemia. We calculated an unbi...
In mouse and humans , each tissue has a distinct distribution of M:F ratios, but in each case the... more In mouse and humans , each tissue has a distinct distribution of M:F ratios, but in each case the distribution for X genes (red line) fits closely to the distribution for A genes (dotted black line). LB, lymphoblastoid cell lines. PBM cells, peripheral blood mononuclear cells. Arrows point to regions where the X and A curves diverge, or to the inflection point in the mouse adipose tissue curve.<b>Copyright information:</b>Taken from "Dosage compensation is less effective in birds than in mammals"http://jbiol.com/content/6/1/2Journal of Biology 2007;6(1):2-2.Published online 22 Mar 2007PMCID:PMC2373894.
M:F ratios in zebra finches, in adult brain, liver, and kidney, and brain of post-hatch day 1 (P1... more M:F ratios in zebra finches, in adult brain, liver, and kidney, and brain of post-hatch day 1 (P1). Autosomal genes (A) are represented by the black dotted line, Z genes (Z) by the red line. The vertical dashed line is centered at a M:F ratio of 1 (logratio of 0). M:F ratios of embryonic chick brain, liver and heart. In each case Z genes are expressed at higher M:F ratios than A genes. In (b) the panel on the far right shows distributions for brain of individual chromosomes containing more than 50 genes. In all panels in (a) and (b) the rightmost bin (at the rightmost mark on the abscissa) includes all genes with M:F ratios at that value or greater, and the leftmost bin includes all genes with M:F ratios at that value or smaller. Z:A ratios of five male and five female chicken samples for heart (H), brain (B) and liver (L).<b>Copyright information:</b>Taken from "Dosage compensation is less effective in birds than in mammals"http://jbiol.com/content/6/1/2Journa...
Sex differences in physiology and disease in mammals result from the effects of three classes of ... more Sex differences in physiology and disease in mammals result from the effects of three classes of factors that are inherently unequal in males and females: reversible (activational) effects of gonadal hormones, permanent (organizational) effects of gonadal hormones, and cell-autonomous effects of sex chromosomes, as well as genes driven by these classes of factors. Often, these factors act together to cause sex differences in specific phenotypes, but the relative contribution of each and the interactions among them remain unclear. Here, we used the Four Core Genotypes (FCG) mouse model with or without hormone replacement to distinguish the effects of each class of sex-biasing factors on transcriptome regulation in liver and adipose tissues. We found that the activational hormone levels have the strongest influence on gene expression, followed by the organizational gonadal sex effect and, lastly, sex chromosomal effect, along with interactions among the three factors. Tissue specifici...
Aging is a risk factor for cognitive decline and susceptibility to neurodegenerative diseases. So... more Aging is a risk factor for cognitive decline and susceptibility to neurodegenerative diseases. Some aspects of aging, like the loss of sex hormones, may be preventable. Menopause is associated with cognitive deficits and brain atrophy. Since standard hormone replacement therapy (HRT) does not mitigate these brain aging outcomes, a gap in knowledge involves understanding brain region-specific, cell-specific, and receptor-specific mechanisms underlying this neurodegeneration. Here, cognitive testing and in vivo magnetic resonance imaging demonstrated that ovarian hormones in female mice at midlife protect against hippocampal-dependent cognitive impairment and dorsal hippocampal atrophy. Further, this neuroprotection in females at midlife is lost in mice with selective deletion of estrogen receptor beta (ERβ) in astrocytes, but not neurons. This preclinical evidence identifies ERβ in astrocytes as a novel therapeutic target to prevent hippocampal-dependent cognitive deficits and reduce...
Three different models of MF1 strain mice were studied to measure the effects of gonadal secretio... more Three different models of MF1 strain mice were studied to measure the effects of gonadal secretions and sex chromosome type and number on body weight and composition, and on related metabolic variables such as glucose homeostasis, feeding, and activity. The 3 genetic models varied sex chromosome complement in different ways, as follows: 1) “four core genotypes” mice, comprising XX and XY gonadal males, and XX and XY gonadal females; 2) the XY* model comprising groups similar to XO, XX, XY, and XXY; and 3) a novel model comprising 6 groups having XO, XX, and XY chromosomes with either testes or ovaries. In gonadally intact mice, gonadal males were heavier than gonadal females, but sex chromosome complement also influenced weight. The male/female difference was abolished by adult gonadectomy, after which mice with 2 sex chromosomes (XX or XY) had greater body weight and percentage of body fat than mice with 1 X chromosome. A second sex chromosome of either type, X or Y, had similar ef...
The majority of preclinical biomedical research involves studies of males rather than females. It... more The majority of preclinical biomedical research involves studies of males rather than females. It is thought that researchers have avoided females based on the idea that female traits are more variable than those of males because of cyclic variation in effects of ovarian hormones. To test the assumption of inherently greater female variability, we analyzed 293 microarray datasets measuring gene expression in various tissues of mice and humans, comprising analysis of more than 5 million probes. Meta-analysis showed that on average, male gene expression is slightly more variable than that of females although the difference is small. We also tested if the X chromosome of humans shows greater variability in gene expression in males than in females, as might be expected because of hemizygous exposure of polymorphic X alleles but again found little sex difference. Our analysis supports and extends previous studies reporting no overall greater phenotypic variability in females.
Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain d... more Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain during health, and regional differences in the transcriptome may occur for each cell type during neurodegeneration. Multiple sclerosis (MS) is multifocal, and regional differences in the astrocyte transcriptome occur in experimental autoimmune encephalomyelitis (EAE), an MS model. MS and EAE are characterized by inflammation, demyelination, and axonal damage, with minimal remyelination. Here, RNA-sequencing analysis of MS tissues from six brain regions suggested a focus on oligodendrocyte lineage cells (OLCs) in corpus callosum. Olig1-RiboTag mice were used to determine the translatome of OLCs in vivo in corpus callosum during the remyelination phase of a chronic cuprizone model with axonal damage. Cholesterol-synthesis gene pathways dominated as the top up-regulated pathways in OLCs during remyelination. In EAE, remyelination was induced with estrogen receptor-β (ERβ) ligand treatment, a...
Progressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairme... more Progressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%-70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing-remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol-treated compared to placebo-treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes. Sixty-two estriol- and forty-nine placebo-treated RRMS patients underwent clinical evaluations and brain MRI. Voxel-based morphometry (VBM) was used to evaluate voxelwise GM sparing from high-resolution T1-weighted scans. A region of treatment-induced sparing (TIS) was defined as the areas where GM was spared in estriol- as compared to placeb...
A modern general theory of sex determination and sexual differentiation identifies the factors th... more A modern general theory of sex determination and sexual differentiation identifies the factors that cause sexual bias in gene networks, leading to sex differences in physiology and disease. The primary sex-biasing factors are those encoded on the sex chromosomes that are inherently different in the male and female zygotes. These factors, and downstream factors such as gonadal hormones, act directly on tissues to produce sex differences and antagonize each other to reduce sex differences. Recent studies of mouse models such as the four core genotypes have begun to distinguish between the direct effects of sex chromosome complement (XX vs. XY) and hormonal effects. Several lines of evidence implicate epigenetic processes in the control of sex differences, although a great deal of information is needed about sex differences in the epigenome.
Philosophical Transactions of the Royal Society B: Biological Sciences, 2016
Historically, it was thought that the number of X chromosomes plays little role in causing sex di... more Historically, it was thought that the number of X chromosomes plays little role in causing sex differences in traits. Recently, selected mouse models have been used increasingly to compare mice with the same type of gonad but with one versus two copies of the X chromosome. Study of these models demonstrates that mice with one X chromosome can be strikingly different from those with two X chromosomes, when the differences are not attributable to confounding group differences in gonadal hormones. The number of X chromosomes affects adiposity and metabolic disease, cardiovascular ischaemia/reperfusion injury and behaviour. The effects of X chromosome number are likely the result of inherent differences in expression of X genes that escape inactivation, and are therefore expressed from both X chromosomes in XX mice, resulting in a higher level of expression when two X chromosomes are present. The effects of X chromosome number contribute to sex differences in disease phenotypes, and may...
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Papers by Yuichiro Itoh